Breast Cancer Exposomics

We are exposed to a mixture of environmental man-made and natural xenobiotics. We experience a wide spectrum of environmental exposure in our lifetime, including the effects of xenobiotics on gametogenesis and gametes that undergo fertilization as the starting point of individual development and, moreover, in utero exposure, which can itself cause the first somatic or germline mutation necessary for breast cancer (BC) initiation. Most xenobiotics are metabolized or/and bioaccumulate and biomagnify in our tissues and cells, including breast tissues, so the xenobiotic metabolism plays an important role in BC initiation and progression. Many considerations necessitate a more valuable explanation regarding the molecular mechanisms of action of xenobiotics which act as genotoxic and epigenetic carcinogens. Thus, exposomics and the exposome concept are based on the diversity and range of exposures to physical factors, synthetic chemicals, dietary components, and psychosocial stressors, as well as their associated biologic processes and molecular pathways. Existing evidence for BC risk (BCR) suggests that food-borne chemical carcinogens, air pollution, ionizing radiation, and socioeconomic status are closely related to breast carcinogenesis. The aim of this review was to depict the dynamics and kinetics of several xenobiotics involved in BC development, emphasizing the role of new omics fields related to BC exposomics, such as environmental toxicogenomics, epigenomics and interactomics, metagenomics, nutrigenomics, nutriproteomics, and nutrimiRomics. We are mainly focused on food and nutrition, as well as endocrine-disrupting chemicals (EDCs), involved in BC development. Overall, cell and tissue accumulation and xenobiotic metabolism or biotransformation can lead to modifications in breast tissue composition and breast cell morphology, DNA damage and genomic instability, epimutations, RNA-mediated and extracellular vesicle effects, aberrant blood methylation, stimulation of epithelial–mesenchymal transition (EMT), disruption of cell–cell junctions, reorganization of the actin cytoskeleton, metabolic reprogramming, and overexpression of mesenchymal genes. Moreover, the metabolism of xenobiotics into BC cells impacts almost all known carcinogenic pathways. Conversely, in our food, there are many bioactive compounds with anti-cancer potential, exerting pro-apoptotic roles, inhibiting cell cycle progression and proliferation, migration, invasion, DNA damage, and cell stress conditions. We can conclude that exposomics has a high potential to demonstrate how environmental exposure to xenobiotics acts as a double-edged sword, promoting or suppressing tumorigenesis in BC.


Introduction
The aim of this review is to deepen our understanding of the study of breast cancer as an "environmental disease", using an exposomics-based hypothesis sustaining that BC is an "ecological disorder" [1][2][3].We are what we eat [4][5][6][7][8], we are what we breathe [9], and we are what we live in [10].This means that food-borne chemicals, all air, soil, and water pollutants; drugs and drug-related metabolites; different types of radiation; aflatoxins; nanoparticles; noise; and many other environmental factors act, individually or synergistically, as genetic and epigenetic carcinogens, in association with inheritance, disparities, reproductive life, age at exposure, and socioeconomic status, which can also increase BCR [11].Many studies concluded that cumulative environmental exposure and lifestyle factors account for 70% to 95% of risk factors that drive the BC incidence rate [12], whereas only 10% to 30% of chronic disease risk can be explained by individual genomic landscape [13].The effects of different types of environmental exposure on BC development, recurrence, overall survival, or treatment resistance [14][15][16] have been reviewed by many authors.Some studies suggest that even climate change will affect women's cancers [17].Cell/mobile phone or smartphone use can result in increased BCR, due to the emission of radiofrequency energy that is absorbed by human tissues situated in the proximity, including breast tissue [18].Many occupational habits, such as heat or night-light exposure, as well as dysregulation of the circadian rhythm, can result in moderate or increased BCR [19,20].Hair dyes [21], cigarette smoking [22,23], radiofrequency radiation [24], laptops, tablets, and other devices [25], hormone-based treatments [26,27], residential and road traffic noise [28,29], and dust [30] were significantly associated with tumorigenesis and invasive BCR.Last but not least, oncogenic viruses have an important role in BC initiation and development [31].
Exposomics is a modern exposome analysis that characterizes all exposures in an untargeted and comprehensive manner [13].Thus, the exposome concept is based on the diversity of exposures to physical factors, synthetic chemicals, dietary components, and psychosocial stressors, as well as their associated biological responses [32].More than two decades ago, Ziegler et al. (1997) reported that BC incidence rates were 4-7 times higher in the United States compared to China and Japan; moreover, when Japanese, Chinese, or Filipino women migrate to the United States, their BCR rates increase over several generations, becoming almost similar with the BCR among American whites [33].Many studies emphasize that the BCR is elevated compared to countries of origin, mainly due to the exposure to a Western lifestyle [33].It is known that exposure to a Western diet is a risk factor for the development and maintenance of chronic and systemic tissue inflammation associated with reprogramming of innate immune cells [34].This lifestyleassociated inflammation is an important cause of multiple cancers, including BC [35].Recently, the concept of "metaflammation" was used to describe a crosstalk between immune and metabolic pathways that connect obesity to metabolic syndrome (MetS), chronic inflammation, and insulin resistance [36].It is well-known that MetS is more prevalent in BC patients and is an independent risk factor or predictor for BC [37][38][39].
Consequently, numerous exogenous risk factors influence the growth, proliferation, and differentiation of breast tissue and BC development.A total of 50% of all cancers in women are hormonally mediated, with both estrogen and androgen playing key roles in initiation and BC development [40].Of all xenobiotic classes, we chose to detail in this review EDCs and food components that can interact with endocrine receptors (ERs) to disturb the normal hormonal equilibrium in BC cells [41].EDCs can be also ingested with food, so increasing and convincing evidence associates food and food-based dietary patterns with BCR [42].Moreover, other food components that act as mutagens [43] can be involved in nutritional regulation of the mammary tumor microenvironment (TME) [44], and also impact growth and proliferation of cancer cells [45].Conversely, food can contain many bioactive compounds with anti-BC potential, exerting a pro-apoptotic role and inhibiting cell cycle progression/cancer cell proliferation, migration, invasion, DNA damage, and cell stress conditions.
It is known that EDC exposure could elevate BCR [46].Most studies assessed environmental EDC exposure, which includes pesticides, plasticizers, pharmaceutical agents, personal care products, food products, and food packaging, via biomarker measurements [46], so that hundreds of EDCs have been assessed as entering human breast tissue from a wide range of environmental sources, enabling all the hallmarks of cancer to develop in human BC cells [47].Furthermore, diets comprising energy-dense and nutrient-poor foods have been associated with an increased BCR [48].Food and food-related/dietary habits, including excessive alcohol use [49], deregulate many signals and metabolic pathways that stimulate the epithelial-mesenchymal transition (EMT), oxidative stress, and reactive oxygen species [50]; dioxin contamination [51], sweetened and highly processed coffee [52] and food [53], meat [54], sweetened drinks [55], EDCs [56], polycyclic aromatic hydrocarbons (PAHs) [57] present in our food, and an inadequate water/liquid daily intake [58] were significantly correlated with carcinogenesis and invasive BC.
Study of absorption, distribution, metabolism/biotransformation, excretion/elimination, and toxicity (ADME-Tox), as well as the bioaccumulation and biomagnification of xenobiotics in cells and liquid or solid tissues emphasize complex interactions with different structures of the human body, such as cellular components (i.e., membranes and proteins), molecular pathways, biological processes, and intra-/extracellular environments [59].Several exposomics-related omics have been developed as a consequence of advances in molecular sciences and analytical techniques based on high-throughput sequencing and mass spectrometry (MS).Thus, environmental toxicogenomics, epigenomics, and interactomics, metagenomics, nutrigenomics and nutriproteomics, micromiRomics, and nutrimiRomics are several new omics fields related with BC exposomics and are involved in molecular characterization of the complex relationship between the human body, environmental exposure, and breast cancer.

Advances and Trends in Omics Fields Related to BC Exposomics
Advances in molecular approaches and analytical techniques based on high-throughput sequencing and mass spectrometry (MS) have generated multi-omics data that can be successfully used to understand the underlying molecular mechanisms involved in BC exposomics [60].BC is mainly caused by mutations in multiple oncogenes and tumor suppressor genes, accompanying epigenetic aberrations of genes and protein pathways [61].Thus, first of all, environmental toxicogenomics aims to collect, analyze, and interpret data on the changes in genes or protein expression, resulting from exposure to xenobiotics, using high-throughput technologies [62].Evidence suggests that various pollutants, such as particulate matter involved in air pollution, act as carcinogenic factors in humans, inducing high rates of genomic instability [63], which is known as an initiator of BC development [61].In addition, environmental epigenomics focuses on environmental factors that induce aberrant DNA methylation of cancer-related genes, even in developing embryos, when result in epigenetic mosaicism that can increase the oncogenic risk later in life [64].Moreover, metagenomics, the study of genetic information of microorganisms present in an environment [65], is involved in the assessment of the human microbiome as a biomarker that experiences longterm exposure to numerous organic contaminants, known as xenobiotics [66].Zhang et al. (2028), using liquid chromatography MS-based global metabolomics coupled with targeted metabolomics, demonstrated that the human microbiome can be significantly perturbed by exposure to xenobiotic mixtures, resulting in dysbiosis and metabolite-modified profiles that play an important role in the host's health [66].With regard to BC, it is well-known that human microbiome-related disturbance may contribute to BC development by producing toxins or promoting inflammation, while certain types of bacteria may have positive effects against BC [67].Recently, network biology techniques were used to identify xenobiotics that target hub proteins in the human interactomes, mainly in disease-associated proteins and contaminant-sensitive biomarkers [68], suggesting a new omics field, environmental interactomics.To exemplify, Moslehi et al. (2021) confirmed the role of arsenic as an ED or xenoestrogen involved in breast carcinogenesis, highlighting the complex arsenic-responsive BC interactome [69].Nutrigenetics studies the effects of nutrition at the gene level, while nutrigenomics is focused on the effects of nutrients on the genome and transcriptome patterns [70].Thus, based on the complex interaction between food components and human genome/proteome, nutrigenomics and nutriproteomics provide new opportunities for development of personalized diets in patients at risk of developing BC [71].
Tissue or circulating microRNA (miRNA) can serve as a novel toxicological biomarker involved in gene activation or suppression, being associated with several key epigenetic mechanisms involved in xenobiotic toxicity [72][73][74].miRNAs are also studied and validated as biomarkers for various diseases, as in the case of miR-423, which is highly expressed in BC and promotes cancer cell proliferation, migration, and invasion by activating NF-κB signaling [75,76].Thus, miRomics is focused on the study of the role of miRNAs in a variety of human diseases, including BC [73].Evidence suggests that organic pollutant exposure, like bisphenol A (BPA), can alter miRNA expression in response to toxicity [77].Recently, nutrimiRomics has been defined as a new omics field focused on the influence of diet components on the dysregulation of gene expression due to epigenetic modification that involves miRNAs, resulting in a higher risk for the development of chronic diseases [78].Thus, Venkatadri et al. (2016) demonstrated that resveratrol, a dietary compound found in a wide variety of plants, can inhibit BC progression by controlling miRNA, regulating the expression of several proteins involved in apoptosis and the cell cycle [79].These authors emphasized the key role in BC cell death in response to resveratrol for miR-542-3p in MCF7 cell line and miR-122-5p in MDA-MB-231 BC cells [79].All these new omics fields complement the traditional approach of genomics, proteomics, transcriptomics, and metabolomics, in order to depict the complicated molecular mechanisms studied by BC exposomics.

Absorption, Distribution, Metabolism/Biotransformation, Bioaccumulation, and Excretion/Bioelimination of Xenobiotics Involved in Breast Cancer
Xenobiotics are substances that are foreign to the intrinsic metabolism of a biological system that has the capacity to bioaccumulate or remove xenobiotics by xenobiotic metabolism, which consists of the deactivation and excretion of xenobiotics and their metabolites [80,81].The human body is exposed to 1-3 million foreign chemical compounds that form a cocktail/mixture of xenobiotics during a lifetime [82].In BC, genotoxic carcinogens include dietary or environmental xenobiotics-heterocyclic amines, aromatic amines, PAHs, and nitropolycyclic aromatic hydrocarbons (NPAHs) [83].Also, many cytotoxic compounds used as anti-cancer drugs for chemotherapy can cause high levels of DNA damage [84], undergo metabolic activation, and are subject to drug metabolism, including uptake, efflux, and detoxification [85].

Absorption
Generally, environmental xenobiotics enter the human body through different absorption surfaces/barriers from input compartments: skin and its appendages, by topical application and absorption, gastro-intestinal mucosa, by ingestion and absorption, and the pulmonary alveolar-capillary membrane, by inhalation.To begin with, EDCs from personal care products are easily absorbed by the skin into systemic circulation after topical application, and can be detected in blood, urine, and breast milk [86,87].However, Rylander et al. (2019) concluded that intensive use of skin care products did not increase the BCR [86].On the other hand, 70-100% of patients receiving radiation therapy following BC experienced radiation-induced skin toxicity [88] comparable to UV exposure, which was associated with decreased postmenopausal BCR, due to higher circulating concentration of a precursor to the active form of vitamin D [89].In addition, the gut absorbs dietary nutrients and provides a barrier to many xenobiotics and microbiome-derived metabolites, so the intestinal epithelium becomes one of the most rapidly proliferating tissues in the body, assuring a rapid and effective elimination of some xenobiotics that bioaccumulate in enterocytes [90].Consequently, the gastro-intestinal tract is also an important route by which drugs, chemicals, pesticides, environmental pollutants, and metabolites of other species are absorbed in the human body [91].Last but not least, air pollution is known as a human carcinogen, especially by gaseous components, as well as through particulate matter, including fine, inhalable particles that can be vectors for radioactive isotopes [92,93].Air polluting agents on their way to the bloodstream pass through the lung barriers [93].White et al. (2022) showed that higher exposure to ambient particle radioactivity (PR-β) was associated with an elevated risk of ER-BC [92].Moreover, Smotherman et al. (2023) found a positive association of particulate matter with postmenopausal BCR [94].

Distribution
The distribution compartment, mainly represented by the systemic bloodstream, transports xenobiotics and their metabolites to all tissues and organs, so that blood is the most used liquid biopsy for biomonitoring of xenobiotics, such as persistent organic pollutants (POPs) [95].From blood, xenobiotics/drugs enter cells, including breast epithelial cells or different cell populations from their ECM or TME.Distribution in cells depend on the chemical nature of xenobiotics, the binding to different receptors or exertion of effects without cellular entry, or using membrane transporters that allow for their entry into the intracellular compartment [85].Moreover, Ish et al. (2023) showed that changes in breast tissue composition may be a potential pathway by which outdoor air pollution impacts BCR [96].Thus, quantitative changes in the relative amount of fibro-glandular tissue can represent a biomarker of BCR that can be used to emphasize the potential biologic pathways underlying the association between environmental exposures and BC [96].In addition, Segovia-Mendoza et al. (2020) showed that the environmental bisphenols, BPA and BBS, induce alteration of the proteomic landscape of different human BC cell lines [97].After bisphenol exposure, vascular endothelial growth factor (VEGF) secretion, CD44, as a biomarker of stemness, and metalloproteinase MMP-14, as a biomarker for invasion, were overexpressed in ER+ BC cell lines, whereas the epidermal growth factor receptor (EGFR) and transforming growth factor beta (TGF-β) were upregulated in ER-BC lines [97].Overall, cell and tissue accumulation of xenobiotics, such as EDCs/POPs, could lead to cellular DNA damage and genomic instability [98], epimutations induced by DNA methylation, acetylation, histone posttranslational modifications (PTMs), RNA-mediated effects, and extracellular vesicle effects [99], alteration of DNA methylation during adipocyte differentiation [100] as well as blood methylation [101], epithelial-mesenchymal transition (EMT) by formation of lamellipodia, disruption of cell-cell junctions, E-cadherin downregulation, reorganization of the actin cytoskeleton in stress fibers as well as overexpression of mesenchymal genes, such as vimentin and fibronectin [102,103], FOXA1 repression and phosphorylation of ERK1/2, p48-MAPK, PI3K/AKT signaling in ER-BC cells [104], and upregulation of Snail and Slug in MCF7 ER+ BC cell line [103].

Biotransformation/Metabolism
Many bioreactive compartments are involved in biotransformation and elimination of xenobiotics.Consequently, many chemicals undergo metabolism and detoxification to produce various metabolites that can cause, in turn, harmful effects such as toxicity [105].Xenobiotic metabolism and detoxification involve xenobiotic-metabolizing enzymes/proteins that are mainly expressed in the liver, but some are also expressed in breast tissue, so that intratumoral xenobiotics or metabolites generated in the liver can undergo further transformation in the breast tissue [83,106].Thus, many enzymes such as mammary-expressed enzymes metabolically activate or detoxify potential genotoxic BC carcinogens, acting in mammary lipid, nipple aspirate, breast milk, and mammary epithelial cells, where most BCs originate [83].Bieche et al. ( 2004) pointed out that the intratumoral dysregulation of genes coding for major xenobiotic-metabolizing enzymes has a role in breast tumorigenesis and drug resistance; thus, N-acetyltransferase 1 (NAT1) was proposed as a candidate biomarker for antiestrogen responsiveness [106].These authors maintained that one-half of the patients with ER+ BC fail to respond favorably to antiestrogen treatment with tamoxifen due to the altered tamoxifen metabolism or bioavailability following the intratumoral alteration in expression of genes coding for xenobiotic-metabolizing enzymes.Moreover, it is known that, in solid tumors, the extracellular and intracellular distribution of xenobiotics and drugs presents a high degree of variability, and is controlled by drug/xenobioticmetabolizing enzymes (DXMEs) as well as cellular influx and efflux systems that transport xenobiotics and drugs into and out of cells [107].

Bioelimination/Excretion
The main routes of elimination of xenobiotics and their metabolites are renal excretion, bile and fecal elimination, and pulmonary exhalation, but there are also secondary routes, such as sweat, hair and nails, breast milk, and tears [105].For example, cadmium was detected at high concentration in BC tissue [108], as well as in the urine of patients with BC, urinary Cd being correlated with the expression of hypoxia-inducible factor 1 alpha (HIF1A) in BC tissues [109].Other heavy metals, such as arsenic, chromium, lead, and mercury are considered to be carcinogens or co-carcinogens and have been detected in the urine of BC patients, even markedly increased [108].Moreover, the environmental exposure to these heavy metals could influence the urine level of metabolites, in association with BC development [108].Human breast milk, a specific breast secretion that reflects the molecular landscape of the normal or pathological mammary gland, contains secretions of the mother's body, in which there are compounds bioaccumulated in her organism, such as organic contaminants (polychlorinated biphenyls, brominated flame retardants, parabens, bisphenols, and perfluoroalkyl and polyfluoroalkyl substances) as well as heavy metals, mycotoxins, and pharmaceuticals residues [110].Thus, many POPs, such as polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and organochlorine pesticides, such as DDT, have been detected in human blood, adipose tissue, and breast milk and tend to become magnified in the food chain over time; breastfeeding infants becoming the final target of POPs [111].Moreover, POPs have been correlated to an increased incidence of hormone-dependent BCs [112].

Bioaccumulation
Usually, many xenobiotics, such as POPs and heavy metals, bioaccumulate within adipose tissue, considered to be widely contaminated with lipophilic xenobiotics in modern society and, consequently, acting as a significant site of xenobiotic storage or sequestration [113].Adipose tissue can play a protective role against xenobiotic effects, because xenobiotic storage in fat can reduce the burden in other critical organs [114].However, female breast adipose tissue is abundant in and in close contact with epithelial cells, representing a major component of the BC TME, which contributes to the development, growth, and invasion of tumor cells [115].Weight loss and insulin resistance are involved in xenobiotic release from adipose tissue into bloodstream [114].Heavy metals, one of the most harmful classes of environmental compounds [116], also stimulate BC progression, exerting a role of DNA methylation level in cancer cells [117].Heavy metals are very difficult to metabolize or decompose, and accumulate in all tissue and organs over the lifetime [116].Evidence suggests that obese people accumulate more heavy metals compared to healthy people [118].Thus, cadmium, among other heavy metals, is a widely spread compound that exerts estrogenic effects, acts as an endocrine disruptor, and accumulates in BC cells over time [109].

Food and Nutrition
Dietary nutritional intake is a key environmental factor with a vital role in cancer prevention and care [70].One-third of cancers in Western high-income societies are associated with food and nutrition, in correlation with physical activity [45], so that increasing and convincing evidence associates food-based dietary patterns with BCR [42].Thus, poor nutrition and foods with a higher energy density have been associated with an increased risk of obesity as well as BC [48,119].Thus, Jacobs et al. (2021), analyzing dietary patterns correlated to BCR in Black urban South African women, concluded that both traditional and cereal-dairy-based meals may reduce the BCR in this population [48].
Overall, thirteen cancers, including BC, have been estimated to be associated with obesity and are known as "obesity-associated cancers" [120].The female breast is rich in adipose tissue [121], so that, in postmenopausal women, the adipose tissue becomes a significant source of estrogen, this obesity-associated estrogen likely playing an essential role in BC growth, mainly in ER+ BC tumors [120].Conversely, caloric restriction or intermittent fasting, a period of voluntary abstention from all food or specific food products [122], can negatively impact BC development, reduce the treatment-induced adverse effects, cytotoxicity, and DNA damage, and increase optimal glycemic regulation, improving serum glucose, insulin, and insulin-like growth factor 1 (IGF-1) levels [123].Insulin and the IGF-1 pathway regulate lifespan and longevity [124].IGF-1 is known as a potent mitogen of high importance in the mammary gland that binds to the cognate receptor, IGF-1R, triggering a signaling intracellular cascade, which increases the proliferative and anti-apoptotic pathways in cancer cells [125].It is known that the Western diet, characterized by high intake of hyperglycemic carbohydrates and insulinotropic dairy, stimulates IGF-1 signaling [124].GH, IGF-1, and insulin have BC-promoting actions, due to increased IGF-1 levels, which have been associated with increased BCR [124].
Food components may act as mutagens, such as N-nitroso-derivatives, polycyclic aromatic hydrocarbons (PAHs), and heterocyclic aromatic amines [43], which can be involved in nutritional regulation of the mammary tumor microenvironment (TME) [44], and impact the growth and proliferation of cancer cells [45].Nutritional stimuli modulate interactions between different cell populations within the TME, such as immune cells, adipocytes, vascular cells, and mammary epithelial and BC stem cells, so that both obesity, a chronic over-nutritional condition, as well as excess caloric consumption, disrupt mammary gland homeostasis and increase BCR [44,123].EDCs has been reported in aquatic macroinvertebrates, mussels and seawater or freshwater fish [126], pork, beef, and chicken meat [127], vegetables [128], as well as in milk and dairy products [129].Heavy metals, such as cadmium, mercury, and lead, act as EDCs and bioaccumulate mainly in fish and seafood products [130].Fish product consumption acts as a double-edged sword.There are studies that emphasize the protective effect of omega-3 fatty acid in fish consumption against BC [131], while the human exposure to fat from milk, eggs, fish, and meat can enhance mammary gland susceptibility to carcinogenesis [132].Alcohol consumption has been related to higher BCR, principally for estrogen receptor-positive (ER+) BCs [133], through stimulation of migration and invasion of MCF7 human BC cells [133], EMT, angiogenesis, OS and ROS production [49,50], decreasing E-cadherin, α, β, and γ catenin expression, as well as BRCA1 tumor suppressor gene expression [133].
Fortunately, in our food, there are many bioactive compounds that are able to exert an anti-cancer potential, re-inducing apoptosis or targeting multiple signaling pathways that allow for cancer cell survival, proliferation, growth, and metastatic progression of BC cells [134].Many dietary compounds are also considered epigenetic modulating agents in cancer [135].Thus, both green or black tea, as well as green or dark coffee, have been associated with a reduced BCR [136,137].Chlorogenic acid (CGA) from coffee exerts an inhibitory role on signaling pathways, such as NF-κB/EMT [138].Epigallocatchin-3-gallate from green tea significantly reduces BCR by decreasing ROS and oxidative DNA damage, mutagenesis, and tumor progression [137].Resveratrol from grapes, berries, and nuts can reduce specific cancer stem cell (CSC) biomarkers in BC cells [139].Piperine inhibits the growth of human BC cells, cell cycle progression, and BC cell migration [140].Carotenoids have been associated with several metabolites involved in membrane signaling, immune regulation, redox balance, and epigenetic regulation [141].One of the most active components of garlic (Allium sativum), allicin (diallylthiosulfinate), induces cell cycle arrest and has pro-apoptotic effects in BC cells, through p53 pathway activation [142], exerting antiproliferative, anticlonogenic, and senolytic effects, inducing the selective death of senescent cells [143].Last but not least, the omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), decreased tumor cell proliferation by downregulation of proliferation-associated protein expression (proliferating cell nuclear antigen (PCNA) and proliferation-related kinase (PRK), induced apoptosis by increasing caspase activity and DNA fragmentation, and decreased signal transduction through the Akt/NF-κB cell survival pathway [144].

Exposure to Endocrine-Disrupting Chemicals (EDCs)
EDCs are man-made chemicals ubiquitously found in the atmosphere as aerosols and particulate matter [145], water [146], pesticides [147], metals such as cadmium (Cd), mercury (Hg), arsenic (As), lead (Pb), manganese (Mn), and zinc (Zn) [148], additives or contaminated food such as dairy products, fish, meat, eggs, and vegetables, bottled water and canned food [149], and cosmetics and personal care products [150].EDCs arrive in the human body through ingestion, inhalation, and/or the transdermal route, bioaccumulate, and interfere with endocrine, immune, and other systems, leading to a disruption of the endocrine signaling and metabolic pathways, and inducing life-long effects and negative consequences even for the next generation [151].EDC exposure also interferes with placental function [152], can interfere with gamete quality, embryo implantation, and fetal development, with serious consequences for offspring viability and health [153].EDCs affect epigenetic markers such as DNA methylation and histone posttranslational modifications (PTMs) [154].In addition, EDCs increase incidence of BC [151].
EDCs are heterogeneous natural or synthetic compounds that include pharmaceutical agents (diethylstilbestrol (DES)), fungicides and pesticides (dichlorodiphenyltrichloroethane (DDT)), plastics (bisphenol A (BPA)), plasticizers (phthalates), and industrial solvents/lubricants (polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), and dioxins).Many EDCs are persistent organic pollutants (POPs), known as lipophilic toxicants that persist in the environment due to their resistance to biodegradation and, moreover, biomagnify or move up the food webs and increase in concentration [113].POPs affect the production of estrogens and estrogenic signals, so that, measured in breast adipose tissue, POP levels were associated with higher BCR and worse prognosis [112].
Several pathogenic effects of EDC exposure are presented in Table 1.Thus, BPA stimulates the proliferation and malignancy of cancer cells through the activation of the Wnt/β-catenin pathway [155], which is widely implicated in the pathogenesis of metastatic BC [156].Significant deregulated gene expression and transcriptional reprogramming in adult fibroblasts exposed to in utero BPA and DES, and specifically, changes in extracellular matrix (ECM) composition due to increased collagen deposition in adult mammary glands, lead to molecular alterations, which develop over time and contribute to increased BCR in adulthood [157].Consequently, in utero exposure of the embryo to high maternal synthetic estrogens/EDCs could be associated with an increased BCR later in life [158].Thus, BC may start in the womb, EDCs affecting the early development of mammary glands [159,160].
It is known that African Americans (AAs) are disproportionately exposed to elevated levels of BPA, so that the urinary BPA level among Black adults and children are statistically significantly higher compared to the non-Black population [161].Recently, Zhang et al. (2023) used a metabolomics-based approach based on both ultra-performance and highperformance liquid chromatography tandem mass spectrometry (UPLC/HPLC-MS/MS) and demonstrated a high connection between tetrabromobisphenol A (TBBPA), a brominated derivative of bisphenol A (BPA) that is extensively present in the environment, with BC development [115].In male and female rats and Rhesus monkey, low-dose exposure to BPA can affect mammary gland development, resulting in significant alterations in the gland morphology, inducing intraductal hyperplasia that could be associated with an increased BCR [162,163].The normal-like human breast epithelial cell line, MCF-10F, after exposure to BPA, showed an increased expression of breast cancer genes BRCA1/2, BRCA1 associated RING domain 1 (BARD1), choline transporter-like protein (CtlP), RAD51 recombinase (RAD51), and BRCA1/2-containing complex subunit 3 (BRCC3), which are all involved in DNA repair, as well as the silencing of programmed cell death protein 5 (PDCD5) and Bcl-2-like 11 (BCL2L11 (BIM)), which are involved in apoptosis [164].
For example, the breasts are particularly susceptible to polycyclic aromatic hydrocarbons (PAHs) that can affect cell morphology, cell division, growth, and repair, cell-cell junctions, and the number of p53 mutations [165].Moreover, Korsh et al. (2015) investigated the link between PAHs and BC based on the use of biomarkers in measuring PAH-DNA adducts to assess the exposure level [165].Polychlorinated biphenyls (PCBs) are persistent industrial pollutants that have been linked to BC progression [166].Thus, many authors concluded that early life exposure to PCBs is a factor of BCR [12,167,168].The highly reactive PCB metabolite, 2,3,5-trichloro-6-phenyl- [1,4]-benzoquinone (PCB29-pQ), induces metastasis of BC and increases cancer stem cell (CSC) biomarker expression, resulting in an increase in EMT in MDA-MB-231 BC cells; the Wnt/β-catenin pathway is also activated by PCB29-pQ, due to overproduction of ROS [166].Many authors concluded that early life exposure to PCBs is a factor of BCR [12,167,168].
Phthalates, phenols, and parabens are considered non-persistent EDCs that have been associated with BC [169].Biomarker concentrations of non-persistent EDCs tend to be higher among women than men, and among Black Americans compared to White Americans, especially based on inconsistent access to healthy food or use of certain products with higher concentration of phthalates, such hair relaxers and skin lightening topical products, that specifically target Black consumers [169].Some phthalates that mimic estradiol may promote BC, as in the case of dibutyl phthalate (DBP) exposure, which is associated with a two-fold increase in the rate of ER+ BC [170].

Conclusions
We are living in close interaction with a cocktail of man-made and natural xenobiotics.We are experiencing a wide spectrum of exposure during our lifetime, including the effects of xenobiotics on gametogenesis and gametes that undergo fertilization as the starting point of individual development and, moreover, in utero exposure that can initiate BC development.We are what we eat, we are what we breathe, and we are what we live.Most xenobiotics are metabolized or/and bioaccumulate and biomagnify in our tissues and cells, including breast tissues, so xenobiotic metabolism can play an important role in BC initiation and progression.This review pointed out the main mechanisms involved in the absorption, distribution, metabolism, bioaccumulation, biomagnification toxicity, and excretion of xenobiotics associated with BC risk, incidence, mortality, initiation, and progression.This association necessitates more valuable explanations at the biomolecular level to highlight the effects of genotoxic and epigenetic carcinogens.However, the accumulated xenobiotics, including their metabolites that arise as a consequence of biotransformation phases, such as heavy metals, endocrine-disrupting chemicals, or food contaminants, as well as a plethora of biomarkers of exposure, can be detected in breast tumoral tissues, adipose tissue, hair, blood, saliva, breast milk, placenta, and urine.In BC tissue biopsies and non-invasive liquid biopsies, xenobiotic exposure has been associated with changes in breast tissue composition and breast cell morphology, genomic instability, DNA damage, alteration of DNA repair, epimutations and epigenetic regulation, cell migration and invasion, angiogenesis, anti-apoptosis, cell adhesion, and cytoskeletal rearrangements, OS and ROS, metabolic reprogramming, immune regulation and metaflammation, membrane transport and signaling, extracellular matrix (ECM) and tumor microenvironment (TME) modifications, or extracellular vesicle (EV) production and content, with consequences in intercellular communication.At a biologic pathway level, most xenobiotics interact with endocrine signaling, adipogenesis, angiogenesis, DNA repair, inflammatory response, IGF-1 and NF-κB signaling, epithelial-mesenchymal transition (EMT), Wnt/β-catenin pathway, PI3K/Akt signaling, fatty acid metabolism (FAM) and glycolysis, MAPK, STAT3, p53 pathway, MYC targets, xenobiotic metabolism, and other cancer-related pathways.Fortunately, in our food, there are also many bioactive compounds with anti-tumor potential, which re-induce apoptosis by activation of caspases or target multiple signaling pathways, such as EMT migration-related pathway, Akt/NF-βB cell survival pathway, or p53 tumor suppressor signaling, that allow for cell survival, proliferation, growth, and metastatic progression of BC cells.
Consequently, BC can be characterized as an environmental disease or an ecological disorder.Evidence for BC risk suggests that food-borne chemical carcinogens, air pollution, ionizing radiation, and socioeconomic status are closely related to breast carcinogenesis.Thus, exposomics and the exposome concept are based on the diversity and range of exposures to physical factors, synthetic chemicals, dietary components, and psychosocial stressors, as well as their associated biological responses.Advances in molecular sciences and analytical techniques based on high-throughput sequencing and mass spectrometry (MS) have generated multi-omics data that can be successfully used to understand the complexity of molecular mechanisms involved in BC exposomics.Thus, environmental toxicogenomics, epigenomics, and interactomics, as well as nutrigenomics and nutriproteomics, metagenomics, micromiRomics, and nutrimiRomics are several new omics fields related to BC exposomics, which can contribute to molecular characterization of the complex relationship between the human body, environmental exposure, and breast cancer.

Table 1 .
Pathological effects of the exposure to ECDs.